This application is a 371 of PCT1EP99/08740 filed Nov. 12, 1999.
1. Field of the Invention
The present invention relates to a process for preparing alkenyl-substituted bis(oxime ether) derivatives of the formula 
where:
R1 is unsubstituted C1-C4-alkyl or C2-C4-alkenyl-, C2-C4-alkynyl- or phenyl-substituted methyl;
R2,R4 independently of one another are hydrogen or methyl;
R3,R5 independently of one another are hydrogen or C1-C4-alkyl, trifluoromethyl or phenyl and
X is xe2x80x94C(xe2x95x90CHCH3)xe2x80x94COOCH3,
xe2x80x94C(xe2x95x90CHOCH3)xe2x80x94COOCH3,
xe2x80x94C(xe2x95x90NOCH3)xe2x80x94COOCH3,
xe2x80x94C(xe2x95x90NOCH3)xe2x80x94CONHCH3 or
xe2x80x94N(OCH3)xe2x80x94COOCH3.
2. Background of the Invention
Alkenyl-substituted bis(oxime ether) derivatives of the formula I are described in the literature as interesting crop protection agents [cf. WO-A 95/21153, WO-A 95/21154, WO-A 96/16030 and WO-A 97/03057].
If the preparation processes described in these publications are applied specifically for synthesizing the alkenyl-substituted bis(oxime ether) derivatives of the formula I, the following difficulties are encountered:
The synthesis route shown in scheme 1, where the component A of the side chain and the component B which contains the pharmacophor are built up separately and only joined at the end, fails owing to the poor accessibility of component A. In the route shown in scheme A, for example, A is inaccessible because of the high ring-closure tendency of the precursors (cf. Tetrahedron Let. (1981) 2557). 
It would furthermore be feasible to build up the side chain successively, starting from building block B, but this has the disadvantage that a large number of synthesis steps have to be performed successively. The expected total yield in such a process is only moderate, and the process is furthermore very tedious.
It is an object of the present invention to provide an economical process which affords alkenyl-substituted bis(oxime ether) derivatives of the formula I in good yield starting from easily accessible starting materials.
We have found that this object is achieved by the process mentioned at the outset which comprises rearranging an alkenylalkyl derivative of the formula II, 
in which the substituents R1 to R5 and X are as defined above, using a base and/or an isomerization catalyst.
As shown in scheme 2, compounds of the formula II can be obtained in an advantageous manner starting from a bis(oxime) monoether of the formula IV and a benzyl derivative of the formula III. 
The synthesis strategy shown in scheme 3 has been found to be particularly advantageous for compounds I having an oxime ether amide pharmacophor. 
By alkylating compound IV with compound IIIa, the oxime ether ester IIa is obtained, which can be converted into the corresponding amide IIb. In the last step, the double bond is isomerized, giving the oxime ether amides of the formula I.
The process according to the invention is illustrated in more detail below.
The isomerization can be carried out in the presence of a base and/or an isomerization catalyst.
Suitable bases are metal hydrides, such as, for example, sodium hydride, or in particular alkali metal alkoxides, such as, for example, potassium tert-butoxide and preferably sodium methoxide or potassium methoxide.
In general, the base is employed in a molar ratio of from 1 to 4 and preferably from 1 to 2, based on the starting material II.
In addition or alternatively to the base, it is also possible to use an isomerization catalyst.
Suitable isomerization catalysts are, in particular, metallic palladium, or else palladium salts, such as palladium(II) chloride or palladium(II) acetate.
The isomerization catalyst is usually employed in a concentration of from 0.1 to 5 mol %.
Suitable solvents are, for example, aliphatic or aromatic hydrocarbons, such as toluene, xylene, heptane, aliphatic or cyclic ethers, such as 1,2-dimethoxyethane, tetrahydrofuran, dioxane or, in particular, polar aprotic solvents, such as acetonitrile, dimethyl sulfoxide, sulfolane, dimethyl formamide or dimethyl acetamide.
The reaction temperature is generally from 20 to 120xc2x0 C. and preferably 20-40xc2x0 C. In the case of the palladium-catalyzed reaction, higher temperatures of from 20 to 160xc2x0 C. and preferably of from 80 to 140xc2x0 C. are used.
The starting materials for the isomerization reaction are compounds of the formula II which are preferably prepared, as shown in scheme 2a, by route A) starting from a bis(oxime) monoether of the formula IV and a benzyl derivative of the formula III, or by route B) starting from an oxime ether of the formula V and a hydroxylamine of the formula VI. 
The reaction A) is a nucleophilic substitution which can be 25 carried out under the customary reaction conditions. The benzyl compounds III are to be understood as compounds in which X is as defined in claim 1 and L1 is a leaving group, such as halogen, acyloxy, alkylsulfonyloxy or arylsulfonyloxy and in particular chlorine or bromine. The substituents R1 to R5 of the bis(oxime) monoethers of the formula IV are as defined in claim 1.
The reaction is expediently carried out in an inert solvent such as an ether, for example tetrahydrofuran or dioxane, or in a polar aprotic solvent, for example acetone, acetonitrile, dimethyl sulfoxide, sulfolane, dimethylformamide or dimethylacetamide.
The base which is employed is usually sodium carbonate or potassium carbonate, sodium hydride, sodium methoxide or a tertiary amine.
The reaction temperature is usually from xe2x88x9220 to 80xc2x0 C.
The reaction can also be carried out in a two-phase system (for example dichloromethane/water) with the aid of a suitable phase-transfer catalyst.
Work-up of the reaction mixtures can be carried out, for example, by extraction.
The benzyl compounds of the formula III are disclosed in EP-A 348766, EP-A 363818 and EP-A 624155.
An advantageous route for preparing the starting materials IV and V is shown in scheme 4. 
Step a):
Step a) is carried out similarly to the procedure described in U.S. Pat. No. 4,707,484.
Suitable for use as solvents are alcohols, such as, for example, methanol, and, in particular, water. In certain cases it may be advantageous to add solubilizers, such as, for example, surfactants or ethylene glycol.
Suitable bases are, in particular, sodium hydroxide and potassium hydroxide, which are usually employed in equimolar amounts or in an excess of up to 10 mol, based on the acetoacetic ester B. Nitrite is to be understood as meaning, for example, an alkali metal nitrite, in particular sodium nitrite, which is usually employed in equimolar amounts or in an excess of up to 30 mol %, based on the acetoacetic ester B.
In general, the reaction temperature should not exceed 40xc2x0 C., since otherwise undesirable side reactions may occur. In water, the reaction is therefore preferably carried out at from xe2x88x9220 to 40xc2x0 C., in particular at from 0 to 15xc2x0 C.
After a period of from 10 to 48 hours, the reaction mixture usually becomes clear. It is then adjusted to a pH of from 0 to 5 and preferably from 1 to 3 using an acid, such as, for example, hydrochloric acid or sulfuric acid.
Work-up is carried out by customary methods, for example by extraction. For purification, the oxime can, for example, be converted into the corresponding salt using bases and reprecipitated using an acid.
The acetoacetic ester B used in the reaction can be prepared as described in Tetrahedron (1985)4633 (see scheme 5) 
The alkenylalkyls of the formula A in which R2 to R5 are as defined in claim 1 and L1 is halogen, acyloxy, alkylsulfonyloxy or arylsulfonyloxy are known, or they can be synthesized by processes known from the literature (Z. Org. Khim. (1997) 486; Bull. Chem. Soc. Jpn. (1980) 2586; J. Am. Chem. Soc. (1984) 2211; J. Am. Chem. Soc. (1960) 1886; DE-A 19 556 66; DE-A 33 173 56; EP-A 271212; Tetrahedron Let. (1986) 6027; Tetrahedron Let. (1994) 1371 and 2679; J. Fluorine Chem. (1997) 67; Helv. Chim. Acta (1951) 1514; Organomet. Chem. (1985) 395).
Step b):
The alkylation is usually carried out in the presence of an inert organic solvent. Suitable solvents are, inter alia, aliphatic or aromatic hydrocarbons, such as, for example, toluene, xylene, heptane or cyclohexane, aliphatic or cyclic ethers, such as, for example, 1,2-dimethoxyethane, tetrahydrofuran or dioxane. Preference is given to using polar aprotic solvents: ketones, such as, for example, acetone, nitriles, such as, for example, acetonitrile, amides, such as, for example, dimethylformamide, dimethylacetamide or N-methylpyrrolidone, or ureas, such as tetramethylurea.
The alkylating agent used is usually a halide, preferably a chloride or bromide, a sulfate, preferably dimethyl sulfate, a sulfonate, preferably a methanesulfonate (mesylate) or a toluenesulfonate (tosylate)
The amount of base or alkylating agent is preferably from one to two times the equimolar amount, based on the compound V.
The reaction is usually carried out in the presence of an inorganic base, such as sodium hydroxide or potassium hydroxide, sodium carbonate or potassium carbonate, sodium bicarbonate or potassium bicarbonate, or of an alkali metal alkoxide, such as sodium methoxide or potassium tert-butoxide.
The reaction temperature is generally between 0xc2x0 C. and 50xc2x0 C., preferably between 0xc2x0 C. and 40xc2x0 C. and in particular at room temperature.
Work-up can be carried out, for example, by extraction.
To remove residual amounts of alkylating agent, it may be advantageous to wash the reaction batch with ammoniacal solution, for example.
Step c):
Hydroxylamine is employed either in the form of an acid addition salt or as free base, it being possible to liberate the latter from the salt by addition of a strong base.
Preference is given to using the acid addition salts of hydroxylamine. All customary acids are suitable for preparing the acid addition salts. Below, only some acids are mentioned, by way of example: carboxylic acids, such as acetic or propionic acid, dicarboxylic acids, such as oxalic or succinic acid, mineral acids, such as phosphoric or carbonic acid and in particular hydrochloric acid or sulfuric acid.
If the acid addition salts of hydroxylamine are employed, it is enerally advantageous to add a base to bind the acid liberated in the reaction. In many cases, a pH of from 3 to 7 and in articular of from 4 to 6 has been found to be advantageous for the oximation. Side reactions such as ring-closure reactions may occur outside of these pH ranges.
In general, from 1 to 2.5 molar equivalents of a base are added. Suitable bases are, in particular, pyridines, trialkylamines, sodium hydroxide, sodium acetate and sodium methoxide. If sodium acetate is used, it is customary to add glacial acetic acid.
Conversely, it is of course also possible to employ the hydroxylamine as free base and to use one of the abovementioned acids to set the abovementioned pH range.
Suitable solvents are, for example, the solvents described in the previous step. In addition, carboxylic acids, such as acetic acid, or else water/pyridine mixtures are also suitable. Particularly suitable are alcohols, such as methanol, ethanol, n-propanol or isopropanol, and mixtures of these with water and/or pyridine.
The reaction temperature is usually from xe2x88x9220 to 50xc2x0 C., preferably from 0 to 40xc2x0 C. and in particular from 20 to 25xc2x0 C.
The work-up of the reaction mixture is preferably carried out by extraction, as described in the previous step. To remove the base completely, it may be advantageous to wash the crude product first, with a dilute aqueous acid and then with water.
Route B) shown in scheme 2a can be carried out similarly to the procedure described in J. Chem. Soc, Chem. Commun. 1986, 903. The preparation of the oxime ethers V is described above; the hydroxylamines of the formula VI are disclosed in EP-A 244786.